1 Overview of breast cancer Sun Yat-Sen Cancer Center

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Overview of breast cancerOverview of breast cancer

Sun Yat-Sen Cancer Center Sun Yat-Sen Cancer Center

Outline

現況Epidemiology Diagnosis, stage Treatment

Surgery Radiation Hormone therapy Chemotherapy

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Breast cancer (Breast cancer ( 乳癌乳癌 )) 是世界重要的健康公共議題是世界重要的健康公共議題台灣地區主要癌症死亡原因。乳癌的發生率為第一位，死台灣地區主要癌症死亡原因。乳癌的發生率為第一位，死

亡率是排名第亡率是排名第 44 位的女性癌症。位的女性癌症。民國 98年，女性及男性乳房惡性腫瘤發生個案數分別占全

部惡性腫瘤發生個案數的 10.24%及 0.06%，女性及男性乳房惡性腫瘤死亡人數占全部惡性腫瘤死亡人數的 3.98%及 0.03%。發生率的排名於女性為第 1 位、男性為第 32位；死亡率的排名於女性為第 4 位、男性為第 34位。

民國 98年初次診斷為女性及男性乳房惡性腫瘤者分別為8,926人及 48人；當年死因為女性及男性乳房惡性腫瘤者分別為 1,588人及 10人。

從從 1970–1996 1970–1996 之間，乳癌發生率增加之間，乳癌發生率增加 2-32-3 倍。倍。 Cancer Registry Annual Report in Taiwan Area 2001Cancer Registry Annual Report in Taiwan Area 2001 Department of Health, Executive Yuan, ROC 2009 Department of Health, Executive Yuan, ROC 2009

臺灣乳癌好發年齡在 40~50歲之間，較歐美國家的好發年齡約提早十歲。

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Taiwan: Cancer Registration (year of diagnosis is 2002; a total of 10 hospitals reported 2,174 cases that includes complete follow-up data for five years) USA: National Cancer Database, Survival Report, 2008 (years of diagnosis are 1998-1999 for a total of 299,900 cases that covers complete follow-up data for five years)

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Normal BreastNormal Breast

A. Breast Duct System A. Breast Duct System B. Lobules B. Lobules C. Breast Duct System C. Breast Duct System D. Nipple D. Nipple E. Fat E. Fat F. Chest Muscle F. Chest Muscle G. Ribs G. Ribs

A. Cells lining duct A. Cells lining duct B. Basement membrane B. Basement membrane C. Open central duct C. Open central duct

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Invasive ductal carcinoma(IDC)Invasive ductal carcinoma(IDC) A. Breast Duct System A. Breast Duct System B. Lobules B. Lobules C. Breast Duct System C. Breast Duct System D. Nipple D. Nipple E. Fat E. Fat F. Chest Muscle F. Chest Muscle G. Ribs G. Ribs

A. Cells lining duct A. Cells lining duct B. Cancer cells, breaking B. Cancer cells, breaking

through the basement through the basement membrane membrane

C. Basement membrane C. Basement membrane

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DCIS and LCISDCIS and LCIS

DCISDCIS （（ Ductal Carcinoma in situ,Ductal Carcinoma in situ, 管內癌），管內癌），及及Premalignant changePremalignant changeTurn out to be cancer in ongoing yearsTurn out to be cancer in ongoing years

LCISLCIS (Lobular carcinoma is situ,(Lobular carcinoma is situ, 原位小葉原位小葉癌）癌）Not a premalignent changeNot a premalignent changeA sign, which indicate risk of breast caA sign, which indicate risk of breast ca

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SymptomsSymptoms

In early breast caIn early breast caEasily self palpatedEasily self palpatedNipple dischargeNipple dischargeMay accompanied with axillary LNMay accompanied with axillary LN

Late breast caLate breast caLocal usually symptomaticLocal usually symptomaticDepends on metastatic sitesDepends on metastatic sites

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EpidemiologyEpidemiology Increases with age, although the rate of increase Increases with age, although the rate of increase

slows after menopause.slows after menopause. Early menarche, late menopause, and nulliparity Early menarche, late menopause, and nulliparity

increase the risk of increase the risk of breastbreast cancercancer.. Atypical lobular or ductal hyperplasia.Atypical lobular or ductal hyperplasia. Other risk factorsOther risk factors

Early exposure to ionizing radiationEarly exposure to ionizing radiation long-term postmenopausal estrogen-replacement therapylong-term postmenopausal estrogen-replacement therapy Alcohol consumption.Alcohol consumption.

The most important risk factor is a family history of The most important risk factor is a family history of breastbreast cancercancer.( 5 to 10%).( 5 to 10%) breastbreast–ovarian –ovarian cancercancer syndrome, the Li–Fraumeni syndrome, the Li–Fraumeni

syndrome, and Cowden's disease.syndrome, and Cowden's disease.

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BiologyBiology BRCA1BRCA1 and and BRCA2BRCA2 germ-line mutations ( 50 – 85% germ-line mutations ( 50 – 85%

lifetime risk of lifetime risk of breastbreast cancercancer, ovarian , ovarian cancercancer, or , or both ). both ).

In sporadic In sporadic breastbreast cancer (cancer (including including p53, bcl-p53, bcl-22, , cc--myc, myc, andand cc-myb-myb),),

HER-2HER-2/neu /neu andand cyclin D1 are overexpressed. cyclin D1 are overexpressed. Factors that stimulate or inhibit growth and Factors that stimulate or inhibit growth and

proliferation of proliferation of breastbreast--cancercancer cells. cells.Gonadal steroid hormones (estrogens, progestins, Gonadal steroid hormones (estrogens, progestins,

and androgens)and androgens)Growth factors (epidermal growth factor, Growth factors (epidermal growth factor,

transforming growth factors and insulin-like growth transforming growth factors and insulin-like growth factors I and II)factors I and II)

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How to describe a breast caHow to describe a breast ca

TNM stageTNM stage

Tumor morphologyTumor morphologyGrade Grade VLIVLIPNIPNI

Special receptorSpecial receptorHormone receptor: ER and PRHormone receptor: ER and PRHer2/NeuHer2/Neu

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TNMTNM

NNN0: no axilla LAPsN0: no axilla LAPsN1:1-3N1:1-3N2:4-9N2:4-9N3>10N3>10

M: M0 or M1M: M0 or M1

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II T1N0T1N0

IIAIIAT1N1T1N1

T2N0T2N0

IIBIIBT2N1T2N1

T3N0T3N0

IIIAIIIA

T1N2T1N2

T2N2T2N2

T3N1T3N1

T3N2T3N2

IIIBIIIB

T4N0T4N0

T4N1T4N1

T4N2T4N2

IIICIIIC N3N3

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疾病種類輔助療法乳癌但無浸潤的情形包括管內癌（ Ductal Carcinoma in situ, DCIS ），及原位小葉癌（ Lobular carcinoma is situ,LCIS ）

不需要

乳癌有浸潤的情形，無淋巴轉移腫瘤小於 1mm 。不需要

最大直徑小於 1cm 浸潤性腺管癌，及浸潤性小葉癌不需要

浸潤性腫瘤，但組織病理預後相對是較好，如髓質癌、黏液素癌、小管癌。腫瘤最大直徑小於 3cm 。

不需要

腫瘤最大直徑大於 1cm 浸潤性腺管癌，及浸潤性小葉癌。

化療、荷爾蒙療法

浸潤性腫瘤，但組織病理預後相對是較好，如髓質癌、黏液素癌、小管癌。腫瘤最大直徑大於 3cm 。


乳癌有浸潤的情形且有腋下淋巴轉移無論腫瘤大小、或病理報告的任何腫瘤


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Tumor morphologyTumor morphology

GradeGradeTubule FormationTubule FormationNuclear PleomorphismNuclear PleomorphismMitotic CountMitotic Count

Vascular lymphatic invasion(VLI)Vascular lymphatic invasion(VLI)Perineural invasion(PNI)Perineural invasion(PNI)

Both indicate aggressive behaviorBoth indicate aggressive behavior

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VLIVLI A. Veins in breast A. Veins in breast B. Lymph channels in breast B. Lymph channels in breast

A. Cells lining duct A. Cells lining duct B. Cancer cells, breaking through B. Cancer cells, breaking through

the basement membrane. the basement membrane. C. Broken basement membrane C. Broken basement membrane D. Cancer entering a lymph D. Cancer entering a lymph

channel. channel. E. Cancer entering a vein. E. Cancer entering a vein. F. Normal breast tissue.F. Normal breast tissue.

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Receptor statusReceptor status

Hormone receptorHormone receptorEstrogen receptor (%)Estrogen receptor (%)Progesterone receptor (%)Progesterone receptor (%)>10% predict response to hormone tx>10% predict response to hormone tx

Her2/neuHer2/neuAssociate with invasion, metastasis…Associate with invasion, metastasis…Predict poor prognosisPredict poor prognosis IHC stain, FISHIHC stain, FISH

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The EGFR (erbB) familyThe EGFR (erbB) family

Membrane

Extracellular

Intracellular

Receptor domain

K

EGFTGF-

Amphiregulin

Tyrosine kinasedomain

erbB4HER4

erbB3HER3

erbB1HER1EGFR

erbB2HER2neu

Ligands

K

No specific ligands Heregulins

K

NRG2NRG3

Heregulins

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Current assay of HER2/Current assay of HER2/neuneu Immunohistochemistry

‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive)

Fluorescence in situ hybridization (FISH)

HER2 gene no amplification FISH negative

HER2 gene amplification FISH positive

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Definition of risk categories for patients with node-negative breast cancer

Annals Oncol 2005; 16: 1669-1583

Low risk Node negative AND all of the following features:Pathologic tumour size ≤2cm, AND Grade 1 ANDAbsence of peritumoural vascular invasion, AND HER2/neu gene neither over-expressed nor amplified, ANDAge ≥35 years

Intermediate risk Node negative AND at least one of the following features:Pathologic tumour size >2cm, OR Grade 2-3, ORPresence of peritumoural vascular invasion, OR HER2/neu gene over-expressed or amplified, ORAge <35 years

Node positive (1-3 nodes involved) ANDHER2/neu gene neither over-expressed nor amplified

High risk Node positive (1-3 nodes involved) ANDHER2/neu gene over-expressed or amplifiedNode positive (4 or more involved nodes)

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Diagnostic ApproachesDiagnostic ApproachesMammographyMammography

25 to 30 % decrease in mortality (>= age of 50 25 to 30 % decrease in mortality (>= age of 50 years and probably also in women between the years and probably also in women between the ages of 40 and 50 years. ages of 40 and 50 years.

High-risk families ( High-risk families ( BRCA1BRCA1 or or BRCA2BRCA2 mutations) mutations)start at 25 years of agestart at 25 years of age5 years earlier than the earliest age at which 5 years earlier than the earliest age at which breastbreast

cancercancer was diagnosed in a family member was diagnosed in a family member The American The American CancerCancer Society and the National Society and the National

Cancer Cancer Institute recommend annual screening Institute recommend annual screening mammography for women older than 40 years who mammography for women older than 40 years who have a standard risk of have a standard risk of breastbreast cancercancer..

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Diagnostic ApproachesDiagnostic Approaches

20years ago, incisional or excisional biopsies 20years ago, incisional or excisional biopsies were the standard methods for confirming the were the standard methods for confirming the diagnosis.diagnosis.

Today, fine-needle aspiration or core needle Today, fine-needle aspiration or core needle biopsy is the standard.biopsy is the standard.

Ultrasound-guided core needle biopsy, Ultrasound-guided core needle biopsy, stereotactic biopsy, and magnetic resonance–stereotactic biopsy, and magnetic resonance–directed biopsy have become important directed biopsy have become important diagnostic tools, especially for women with diagnostic tools, especially for women with suspicious but nonpalpable suspicious but nonpalpable breastbreast masses. masses.

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TreatmentTreatment

Localized breast cancerLocalized breast cancerSurgery is mainstaySurgery is mainstayHalsted, 1882, radical mastectomyHalsted, 1882, radical mastectomy

John HopkinsJohn Hopkins

Metastatic breast cancerMetastatic breast cancerSystemic treatmentSystemic treatment

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Radical mastectomyRadical mastectomy

A. Entire breast and a A. Entire breast and a chest wall muscle is chest wall muscle is removed. removed.

LNs in the level 1 (B) and LNs in the level 1 (B) and level 2 (C ), and even level 2 (C ), and even sometimes more distant sometimes more distant lymph node groups (D, E lymph node groups (D, E and F) were also and F) were also removed. removed.

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Modified radical mastectomy Modified radical mastectomy (MRM)(MRM)

A. Entire breast is A. Entire breast is removed removed

Classically some Classically some lymph nodes in the lymph nodes in the level 1 (B) and level 2 level 1 (B) and level 2 (C ) were removed, (C ) were removed, called an axillary called an axillary lymph node lymph node dissection. dissection.

MRM = simple mastectomy + ALND

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Breast conserving surgeryBreast conserving surgery

Also called Also called lumpectomylumpectomy

RT should be RT should be followedfollowed

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Surgical evolutionSurgical evolution

Radical mastectomyRadical mastectomy1885 ~ 1960s1885 ~ 1960s

Modified radical mastectomy: 1970sModified radical mastectomy: 1970s

Lumpectomy + RT, 1970sLumpectomy + RT, 1970sNSABP B-06, NEJM 1985NSABP B-06, NEJM 1985

Lumpectomy vs. MRMLumpectomy vs. MRMMilan Cancer Institute, NEJM 1977Milan Cancer Institute, NEJM 1977

Lumpectomy vs. RMLumpectomy vs. RM

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Radical mastectomy : Radical mastectomy : breast breast Conserving therapy Conserving therapy

Equivalent survival with BCT (breast-conservingtherapy) as compared to mastectomy.

lumpectomy (wide excision of the tumor with preservation of the breast) with radiotherapy is the preferred treatment.

Radiotherapy, an integral part of BCT, is inappropriately withheld from some women, especially those older than 65 years.

Noninvasive (in situ) ductal and lobular breast cancer can also be treated adequately with lumpectomy and radiotherapy.

Early Breast Cancer Trialists' Collaborative Group. N Engl J Med 1995; 333:1444.Early Breast Cancer Trialists' Collaborative Group. N Engl J Med 1995; 333:1444.

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Individual and Pooled Odds Ratios for Survival at 10 Individual and Pooled Odds Ratios for Survival at 10 Years in Women with Breast Cancer Treated by Breast-Years in Women with Breast Cancer Treated by Breast-

Conserving Therapy as Compared with Mastectomy.Conserving Therapy as Compared with Mastectomy. Cancer 1977;40:Suppl:574-587

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Axillary Lymph-Node Dissection Axillary Lymph-Node Dissection Recurrence is higher with positive axillary lymph nodes and Recurrence is higher with positive axillary lymph nodes and

increases with each additional positive node.increases with each additional positive node. Axillary lymph-node dissectionAxillary lymph-node dissection

only provides prognostic informationonly provides prognostic information most of the morbidity associated with most of the morbidity associated with breastbreast surgery. surgery. remains the standard of care for all women with invasive remains the standard of care for all women with invasive breastbreast

cancercancer or large noninvasive tumors (>2.5 cm). or large noninvasive tumors (>2.5 cm).

Sentinel-lymph-node mapping ( radioactive substance or a Sentinel-lymph-node mapping ( radioactive substance or a blue dye is injected into the area around the tumor)blue dye is injected into the area around the tumor) The lower ipsilateral axilla is explored through a small incision The lower ipsilateral axilla is explored through a small incision

and the lymph node that has taken up the dye or radioactive and the lymph node that has taken up the dye or radioactive substance is excised.substance is excised.

The positive predictive value (100 %), negative predictive value The positive predictive value (100 %), negative predictive value (> 95 %). (> 95 %).

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Adjuvant Radiotherapy Adjuvant Radiotherapy Radiotherapy is an integral part of Radiotherapy is an integral part of breastbreast-conserving -conserving

treatment.treatment. Administering chemotherapy before radiotherapy resulted in Administering chemotherapy before radiotherapy resulted in

higher survival rates when given postoperatively.higher survival rates when given postoperatively. Postmastectomy radiotherapy reduces the incidence of local Postmastectomy radiotherapy reduces the incidence of local

and regional recurrences by 50 to 75 % ( not increase and regional recurrences by 50 to 75 % ( not increase survival).survival).

Only for women at high risk for local or regional recurrence Only for women at high risk for local or regional recurrence ( large tumors invading the skin of the ( large tumors invading the skin of the breast, breast, chest wall, chest wall, positive axillary lymph nodes).positive axillary lymph nodes).

Benefit for high-risk premenopausal women. Fewer local and Benefit for high-risk premenopausal women. Fewer local and regional recurrences and overall survival was significantly regional recurrences and overall survival was significantly better among the women treated with radiotherapy and better among the women treated with radiotherapy and chemotherapy. chemotherapy.

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Hortobagyi, G. N. N Engl J Med 1998;339:974-984

Ten-Year Cancer-free Survival and Overall Survival among Ten-Year Cancer-free Survival and Overall Survival among Women Treated with Chemotherapy with or without Women Treated with Chemotherapy with or without

Radiotherapy after MastectomyRadiotherapy after Mastectomy

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Impact of surgical evolutionImpact of surgical evolution

Local control: no survival benefitLocal control: no survival benefitLocal control: RM>MRM>BCT+RT>BCTLocal control: RM>MRM>BCT+RT>BCTSurvival no differentSurvival no different

Why? distant metastasis is the main cause Why? distant metastasis is the main cause

Distant “micrometastasis” Distant “micrometastasis” Not from local residual dzNot from local residual dzDoes exist at diagnosisDoes exist at diagnosis

Adjuvant systemic treatmentAdjuvant systemic treatment

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Adjuvant systemic treatmentAdjuvant systemic treatment

Hypothesis: Hypothesis: Eradicate micrometastasisEradicate micrometastasisFrom effective tx for overt(macro) metastasis From effective tx for overt(macro) metastasis

ChemotherapyChemotherapyHormone therapyHormone therapy

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Adjuvant chemotherapyAdjuvant chemotherapy

CMF, first generation, 1970sCMF, first generation, 1970sCyclophosphamideCyclophosphamideMethotrexateMethotrexate5-FU5-FU

Benefit in Benefit in Distant recurrence Distant recurrence Survival Survival

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CAF or CEF, 2nd generation, 1980sCAF or CEF, 2nd generation, 1980sCyclophophamideCyclophophamideAdramycin(or Epirubicin)Adramycin(or Epirubicin)5-FU5-FU

More toxic than CMFMore toxic than CMFCAF better than CMF in high-risk groupCAF better than CMF in high-risk group

Axilla LN+Axilla LN+LN-, but tumor large or other risk factorLN-, but tumor large or other risk factor

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Benefits both premenopause and postmenopauseBenefits both premenopause and postmenopause Benefit is greater in younger as compared to older Benefit is greater in younger as compared to older

women. women. < 50 , polychemotherapy reduced the risk of disease < 50 , polychemotherapy reduced the risk of disease

relapse and death by 37 and 30%, respectively. relapse and death by 37 and 30%, respectively. 10 % absolute improvement in 15-year survival (42 versus 10 % absolute improvement in 15-year survival (42 versus

32 %). 32 %). Age 50 to 69, the risk of relapse or death was Age 50 to 69, the risk of relapse or death was

decreased by 19 and 12 %.decreased by 19 and 12 %. 3 % absolute gain in 15-year survival (50 versus 47 %). 3 % absolute gain in 15-year survival (50 versus 47 %).

> age 70 , the benefits of chemotherapy are still > age 70 , the benefits of chemotherapy are still uncertain because few studies have included uncertain because few studies have included women in this age group. women in this age group.

Lancet 2005; 365:1687Lancet 2005; 365:1687

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Early Days: Alkylating Agents and Early Days: Alkylating Agents and AntimetabolitesAntimetabolites

In 1976, Bonadonna and colleagues from In 1976, Bonadonna and colleagues from Milan, Italy, reported that postoperative Milan, Italy, reported that postoperative CMF improved DFS and OS CMF improved DFS and OS in women with node-positive breast cancerin women with node-positive breast cancer

At the same time, the NSABP was At the same time, the NSABP was evaluating adjuvant evaluating adjuvant L-phenylalanine mustard and fluorouracilL-phenylalanine mustard and fluorouracil

In Scandinavia, Nissen Meyer was In Scandinavia, Nissen Meyer was evaluating adjuvant cyclophosphamide evaluating adjuvant cyclophosphamide

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Duration of ChemotherapyDuration of ChemotherapyCA Cancer J Clin 1995;45:199-226 EBCTCG. Lancet 1992;339:71-85

less than 3 months was inferior to treatment for 4 to 6 monthsless than 3 months was inferior to treatment for 4 to 6 months Longer than 6 months was no more effective than treatment Longer than 6 months was no more effective than treatment

for four to 6 months.for four to 6 months. The combinations standard therapyThe combinations standard therapy

fluorouracil, doxorubicin, and cyclophosphamide (FAC 6 cycles)fluorouracil, doxorubicin, and cyclophosphamide (FAC 6 cycles) fluorouracil, epirubicin, and cyclophosphamide (FEC 6 cycles)fluorouracil, epirubicin, and cyclophosphamide (FEC 6 cycles) (AC 4 cycles); and CMF (6 cycles).(AC 4 cycles); and CMF (6 cycles). intermittently at intervals of three to four weeks. intermittently at intervals of three to four weeks.

Addition of 4 cycles of paclitaxel (duration, 12 to 16 weeks) to Addition of 4 cycles of paclitaxel (duration, 12 to 16 weeks) to 4 cycles of AC improved both disease-free survival and 4 cycles of AC improved both disease-free survival and overall survival rates.overall survival rates.

In premenopausal womenIn premenopausal women Ovarian ablation = combination chemotherapy or tamoxifen.Ovarian ablation = combination chemotherapy or tamoxifen. This benefit persists for 15 years after treatment. This benefit persists for 15 years after treatment.

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The choice of regimenThe choice of regimen

Ththere is a modest but significant benefit Ththere is a modest but significant benefit for anthracycline-containing compared to for anthracycline-containing compared to nonanthracycline-containing adjuvant nonanthracycline-containing adjuvant chemotherapy (CMF).chemotherapy (CMF).

Both premenopausal and postmenopausal Both premenopausal and postmenopausal women with node-positive breast cancer women with node-positive breast cancer should consider a taxane-containing should consider a taxane-containing chemotherapy regimen. chemotherapy regimen.

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Incorporate TaxaneIncorporate TaxaneTAC, 3rd generation, mid-1990sTAC, 3rd generation, mid-1990s

TaxotereTaxotereAdriamycinAdriamycinCyclophosphamideCyclophosphamide

More toxic than CAFMore toxic than CAFBetter than CAF in high-risk groupBetter than CAF in high-risk group

Need more time to observeNeed more time to observe

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Adjuvant HerceptinAdjuvant Herceptin

Effective in Her2+ ptsEffective in Her2+ pts ICH3+ICH3+FISH+FISH+

Herceptin + adjuvant chemotherapyHerceptin + adjuvant chemotherapyOptimal role to be definedOptimal role to be defined

Concurrent or sequential?Concurrent or sequential?Maintenance ? Duration ?Maintenance ? Duration ?

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Adjuvant hormone therapy Adjuvant hormone therapy

(B) Postmenopausal(B) Postmenopausal

GNRH agonistsGNRH agonists

Breastcarcinoma

Breastcarcinoma

AntiestrogenAntiestrogen

Ovary

LHFSHLH

FSH

AntiestrogenAntiestrogen

(A) Premenopausal(A) Premenopausal

AdrenalAdrenalEstrogenEstrogen EstrogenEstrogen

AndrostenedioneAndrostenedione

AromataseinhibitorAromataseinhibitor

PeripheralaromatizationPeripheralaromatization

Adapted with permission from Tellez C, et al. Surg Oncol Clin North Am. 1995;4:751-777.

GNRH = Gonadotropin-releasing hormone; LH = Luteinizing hormone; FSH = Follicle-stimulating hormone.

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Hormone therapy — Adjuvant Hormone therapy — Adjuvant hormone therapyhormone therapy

For presence of ER or progesterone (PgR) For presence of ER or progesterone (PgR) receptors. receptors.

Premenopausal womenPremenopausal women Surgical removal (or irradiation) of the ovariesSurgical removal (or irradiation) of the ovaries TamoxifenTamoxifen Luteinizing hormone releasing hormone (LHRH) analogs Luteinizing hormone releasing hormone (LHRH) analogs

(eg, goserelin [Zoladex®], leuprolide [Lupron®]). (eg, goserelin [Zoladex®], leuprolide [Lupron®]).

For postmenopausal womenFor postmenopausal women Tamoxifen or aromatase inhibitors (anastrozole Tamoxifen or aromatase inhibitors (anastrozole

[Arimidex®], letrozole [Femara®], exemestane [Arimidex®], letrozole [Femara®], exemestane [Aromasin®]). [Aromasin®]).

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Tamoxifen hormone therapyTamoxifen hormone therapyEBCTCG

The Lancet 2005; 365:1687-1717

ER (+) onlyER (+) only 5 yrs of adjuvant tamoxifen reduces the annual 5 yrs of adjuvant tamoxifen reduces the annual

breast cancer death rate by 31%, largely breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age irrespective of the use of chemotherapy and of age (<50, 50(<50, 50––69, ≥70 years), progesterone receptor 69, ≥70 years), progesterone receptor status, or other tumor characteristics.status, or other tumor characteristics.

The annual breast cancer mortality rates are similar The annual breast cancer mortality rates are similar during years 0during years 0––4 and 54 and 5––14. 14.

The cumulative reduction in mortality is more than The cumulative reduction in mortality is more than twice as big at 15 years as at 5 years twice as big at 15 years as at 5 years

5 years vs 1-2 yrs 5 years vs 1-2 yrs 2p<02p<0··00001 for recurrence00001 for recurrence 2p=02p=0··01 for breast cancer mortality01 for breast cancer mortality

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Adjuvant hormone therapyAdjuvant hormone therapy

Aromatase inhibitorAromatase inhibitorEffective in post-menopausal stateEffective in post-menopausal stateAromatase, in fat tissue, Aromatase, in fat tissue,

Convert androgen to estrogenConvert androgen to estrogenMain estrogen source in post-menopausalMain estrogen source in post-menopausal

Exemestane : AromasinExemestane : AromasinLetrozole: FemaraLetrozole: FemaraAnastrozole: Arimidex Anastrozole: Arimidex

More effective than TamoxifenMore effective than Tamoxifen

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ATAC

Significantly higher toxicity with tamoxifen vs anastrazole

• Vaginal bleeding or discharge

• Hot flashes

• Endometrial cancer

• Ischemic cerebrovascular events

• Venous thromboembolic events

Significantly higher toxicity with anastrozole vs tamoxifen

• Arthralgia

• Fractures

Comparative Toxicity: Tamoxifen Comparative Toxicity: Tamoxifen and Aromatase Inhibitors and Aromatase Inhibitors

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Comparative Toxicity: Tamoxifen Comparative Toxicity: Tamoxifen and Aromatase Inhibitors and Aromatase Inhibitors

Significantly higher toxicity with tamoxifen vs exemestane

• Gynecologic symptoms

• Vaginal bleeding

• Muscle cramps

• Thromboembolic events

Significantly higher toxicity with exemestane vs tamoxifen

• Arthralgia, Myalgia, Arthritis/osteoarthritis

• Limb pain, Carpal tunnel, Paraesthesia

• Myocardial infarction

• Diarrhea

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Aromatase inhibitors Aromatase inhibitors

Upfront therapy (an AI initially instead of Upfront therapy (an AI initially instead of tamoxifen) tamoxifen)

Sequential therapy (switch to an AI after 2-Sequential therapy (switch to an AI after 2-3 years of tamoxifen)3 years of tamoxifen)

Extended therapy (an AI after 5 years of Extended therapy (an AI after 5 years of tamoxifen).tamoxifen).

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Adjuvant ovarian suppressionAdjuvant ovarian suppression

Effective in pre-menopausal stateEffective in pre-menopausal stateType Type

Surgical ablationSurgical ablationRT ablationRT ablationGnRH analogue: Goserelin, LeuprideGnRH analogue: Goserelin, Leupride

Exact role to be definedExact role to be definedCombination with chemotherapy?Combination with chemotherapy?Combination with AI or TAM?Combination with AI or TAM?

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Concurrent chemotherapy : Concurrent chemotherapy : Sequential chemotherapySequential chemotherapy

Proc Am Soc CLIN Oncol 21: 37a, 2002 (abstr 143)Proc Am Soc CLIN Oncol 21: 37a, 2002 (abstr 143)

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Does chemotherapy add benefit to Does chemotherapy add benefit to tamoxifen for postmenopasual women tamoxifen for postmenopasual women

with ER-positive disease ?with ER-positive disease ? Combined chemotherapy and tamoxifen therapy Combined chemotherapy and tamoxifen therapy

for postmenopausal women with node-positive for postmenopausal women with node-positive ER-positive disease. 2000 EBCTCG overview ER-positive disease. 2000 EBCTCG overview analysisanalysis Decreased the annual risk of recurrence and death by Decreased the annual risk of recurrence and death by

35 and 34%, vs tamoxifen alone.35 and 34%, vs tamoxifen alone. Tamoxifen should be started after chemotherapy is Tamoxifen should be started after chemotherapy is

completed, and not given concurrently. completed, and not given concurrently. The benefit of adding chemotherapy to The benefit of adding chemotherapy to

tamoxifen is less clear for women with ER-tamoxifen is less clear for women with ER-positive node-negative positive node-negative are inconclusiveare inconclusive

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Neoajuvant chemotherapyNeoajuvant chemotherapy

Large operable tumorsLarge operable tumors90% of primary operable tumors decrease 90% of primary operable tumors decrease

in size by more than 50 %.in size by more than 50 %.Lumpectomy a possibility for many women Lumpectomy a possibility for many women

who would otherwise have required a who would otherwise have required a mastectomy. mastectomy.

No apparent advantage survival to No apparent advantage survival to preoperative chemotherapy as compared preoperative chemotherapy as compared with postoperative chemotherapy. with postoperative chemotherapy.

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Neoajuvant chemotherapyNeoajuvant chemotherapy Emerging data supports a similar degree of benefit from Emerging data supports a similar degree of benefit from

taxanes in the neoadjuvant setting.taxanes in the neoadjuvant setting. 4 cycles of induction AC plus vincristine and prednisolone 4 cycles of induction AC plus vincristine and prednisolone

(CAVP); responders were then randomly assigned to continue (CAVP); responders were then randomly assigned to continue CAVP for a total of eight courses, or switch to four cycles of CAVP for a total of eight courses, or switch to four cycles of docetaxel. docetaxel.

The number of pCRs The number of pCRs (pathologic complete remission) sequential sequential docetaxel vs CAVP (34 versus 16 %). docetaxel vs CAVP (34 versus 16 %).

Initial fail respond to CAVP had a Initial fail respond to CAVP had a cCR (complete clinical responses) rate of 55% to subsequent docetaxel monotherapy. rate of 55% to subsequent docetaxel monotherapy.

Significant five-year OS (97 versus 78 %)Significant five-year OS (97 versus 78 %) Presented at the 26th annual San Antonio Breast Cancer Symposiom, San Antonio, Presented at the 26th annual San Antonio Breast Cancer Symposiom, San Antonio,

TX, December 2003 (abstract 11). TX, December 2003 (abstract 11).

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Treatment of metastatic dzTreatment of metastatic dz Usual sites: bone, lung, liver, brainUsual sites: bone, lung, liver, brain Incurable Incurable

Goal: live with dz for longest timeGoal: live with dz for longest time

Systemic treatment is mainstaySystemic treatment is mainstay ChemotherapyChemotherapy Hormone therapyHormone therapy

Palliative local therapyPalliative local therapy Radiotherapy Radiotherapy Palliative surgeryPalliative surgery

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Treatment strategyTreatment strategy

Principle: Principle: Save your bulletSave your bulletRight time, right treatmentRight time, right treatment

Why?Why?Treatment effectiveness only in limited Treatment effectiveness only in limited

durationdurationTo avoid unnecessary toxicityTo avoid unnecessary toxicityUltimately incurableUltimately incurable

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Chemotherapy Chemotherapy

In general, chemotherapyIn general, chemotherapySingle agent: RR: 20-30%Single agent: RR: 20-30%Combination: doublet: 40-60%Combination: doublet: 40-60%

triplet: 70-80% triplet: 70-80%

Hormone therapyHormone therapyTamoxifen: RR 15-20%Tamoxifen: RR 15-20%Aromatase inhibitor: RR 30-35%Aromatase inhibitor: RR 30-35%

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Chemotherapeutic agentsChemotherapeutic agents

Single agents:Single agents:Doxorubicin/EpirubucinDoxorubicin/EpirubucinCyclophosphamideCyclophosphamideMTXMTX5-FU5-FUTaxane(Paclitaxel, Docetaxel)Taxane(Paclitaxel, Docetaxel)NavelbineNavelbineGemcitabine Gemcitabine

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Chemotherapy regimensChemotherapy regimens

Combination:Combination:Navelbine-HDFLNavelbine-HDFLPaclitaxel-CisplatinPaclitaxel-CisplatinDoxorubicin-CyclophosphamideDoxorubicin-CyclophosphamideGemcitabine-Paclitaxel/-Trastuzumab/-Gemcitabine-Paclitaxel/-Trastuzumab/-

lapatinib lapatinib

Combination C/T provide better RR, but Combination C/T provide better RR, but overall survival not differentoverall survival not different

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Example - 1Example - 1

55y/o woman, ER/PR +/+, 55y/o woman, ER/PR +/+, Dz recurred 5yrs after surgeryDz recurred 5yrs after surgeryOnly neck and mediastinum LNsOnly neck and mediastinum LNsSlowly progressed clinically(!)Slowly progressed clinically(!)

Hormone therapyHormone therapy

May do RT for symptomatic siteMay do RT for symptomatic site

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45 y/o woman, ER/PR -/-45 y/o woman, ER/PR -/-Dz recurred 3 yrs after operationDz recurred 3 yrs after operationOnly right supraclavicle LNsOnly right supraclavicle LNsSlowly progressed Slowly progressed

RT alone

Observation

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50 y/o woman, ER/PR +/+50 y/o woman, ER/PR +/+ Back, shoulder, hips pain, 3m, progressBack, shoulder, hips pain, 3m, progress Massive bone mets over spine, pelvis, Massive bone mets over spine, pelvis,

shoulder, and ribsshoulder, and ribs

Systemic chemotherapy, combination

RT for symptomatic sites

Bisphosphonate: Aredia or Zometa

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55 y/o woman, ER/PR +/+55 y/o woman, ER/PR +/+ Dyspnea progressivelyDyspnea progressively Lung mets bilaterallyLung mets bilaterally

Systemic chemotherapy, combination

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Treatment principleTreatment principle

For visceral organ crisisFor visceral organ crisisCombination chemotherapyCombination chemotherapyFailure is not allowedFailure is not allowed

(high RR necessary)(high RR necessary)

For isolated LN or bone metsFor isolated LN or bone metsHormone tx (more chance to try)Hormone tx (more chance to try)RT alone in hormone unresponderRT alone in hormone unresponder

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TrastuzumabTrastuzumab 20-30 % of breast cancers overexpress the 20-30 % of breast cancers overexpress the

HER-2/neu protein. HER-2/neu protein. Preliminary reports support a significant Preliminary reports support a significant

disease-free survival and overall survival benefit disease-free survival and overall survival benefit from the addition of trastuzumab to from the addition of trastuzumab to anthracyclines and paclitaxel in the adjuvant anthracyclines and paclitaxel in the adjuvant setting, particularly for women with node-positive setting, particularly for women with node-positive breast cancer.breast cancer.

Increase in the risk of cardiac events. Increase in the risk of cardiac events. Trastuzumab at the earliest sign of cardiotoxicity Trastuzumab at the earliest sign of cardiotoxicity developed in 2 to 3 % over a two year period. developed in 2 to 3 % over a two year period. Long-term data in the adjuvant setting is lacking. Long-term data in the adjuvant setting is lacking.

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SUMMARY SUMMARY Surgical resection is required in all invasive breast cancer. Surgical resection is required in all invasive breast cancer.

Outcomes are similar with mastectomy and breast conserving Outcomes are similar with mastectomy and breast conserving therapy (lumpectomy plus breast radiation therapy). therapy (lumpectomy plus breast radiation therapy).

The status of the axillary lymph nodes provides important The status of the axillary lymph nodes provides important prognostic information. prognostic information. Sentinel lymph node dissection is replacing axillary lymph node Sentinel lymph node dissection is replacing axillary lymph node

dissection.dissection. there is no information about the long-term outcome (ie, cancer-there is no information about the long-term outcome (ie, cancer-

specific survival). (compare to full axillary node dissection.)specific survival). (compare to full axillary node dissection.) With positive sentinel node require a completion axillary node With positive sentinel node require a completion axillary node

dissection. dissection. Adjuvant systemic therapy (chemotherapy, hormone Adjuvant systemic therapy (chemotherapy, hormone

therapy, trastuzumab or a combination) is recommended for therapy, trastuzumab or a combination) is recommended for node (+), and tumors > 1 cm. node (+), and tumors > 1 cm.

Adjuvant hormone therapy is for ER-positive or PR-positive. Adjuvant hormone therapy is for ER-positive or PR-positive.

Documents

1 Overview of breast cancer Sun Yat-Sen Cancer Center